Organocopper reagents are highly desirable reagents for organic synthesis. They often react stereoselectively. Furthermore, they do not possess the extreme nucleophilicity of reagents such as Grignard reagents. Consequently, they can be used to synthesize organic compounds that are highly functionalized.
The chemistry of allyl organocopper reagents is illustrative of these characteristics. Allyl organocopper reagents have received renewed interest with Lipshutz's development of higher order allylic cyanocuprates, which have been shown to be among the most reactive cuprates yet developed. See, for example, B. H. Lipshutz et al., J. Org. Chem., 54, 4977 (1989); B. H. Lipshutz et al., J. Am. Chem. Soc., 112, 4063 (1990); and B. H. Lipshutz et al., J. Am. Chem. Soc., 112, 4404 (1990).
The synthetic routes for production of organocopper reagents generally involve metathesis reactions of organolithium or Grignard reagents. Accordingly, functionalized organic substrates cannot be tolerated. For example, the allyl organocopper reagent is obtained only by an indirect synthesis involving the transmetalation of allylic stannates with an alkylcopper reagent, which was previously formed from a transmetalation of an organolithium or Grignard reagent. The problem with direct synthesis from an inorganic copper agent and an organic halide has been that the inorganic copper agent has either caused homocoupling of the organic halides or has not undergone oxidative addition with the organic halide.
An organocopper reagent can be produced directly from a highly reactive form of zerovalent copper, which is obtained from the reduction of copper(I) iodide phosphine complexes with a solution of lithium naphthalenide in tetrahydrofuran under argon. See, for example, R. D. Rieke et al., Tetrahedron, 45, 443 (1989); and R. D. Rieke et al., Synth. Commun., 20, 2711 (1990). The active copper produced by this method will undergo oxidative addition to primary bromides, vinyl iodides, vinyl bromides, as well as aryl iodides and bromides. The organic halides can contain a limited number of functional groups such as esters, nitriles, and chlorides. The resulting organocopper reagents undergo typical lower order and higher order cuprate additions with electrophiles. However, the presence of the phosphine by-product represents a severe complication for product purification.
Therefore, an object of the invention is to produce a zerovalent copper reagent which is more reactive than that obtained with the copper(I) iodide phosphine method. A further object is the development of a zerovalent copper reagent that is free of phosphines. Another object is the direct production of highly functionalized aryl and alkyl cuprates from the corresponding halides. Yet another object is the direct production of highly functionalized allyl cuprates from the corresponding halides and acetates. Still another object is the production of bis- and tris- organocopper reagents by direct synthesis from zerovalent copper metal and organic compounds having two or more halogens.